According to the National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994), between one third and one half of men and women in the United States are overweight. In the United States, sixty percent of men and fifty-one percent of women, of the age of 20 or older, are either overweight or obese. In addition, a large percentage of children in the United States are overweight or obese.
The cause of obesity is complex and multi-factorial. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk.
There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes disease risk, increases independently with increased body mass index (BMI). Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for females, and a seven percent increase in the risk of cardiac disease for males, for each point of a BMI greater than 24.9 (see Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002). In addition, there is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. Recently it has been shown that considerable weight loss can effectively cure type 2 diabetes (Lim et al, Diabetologia June 2011).
Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, many of these drugs have proven to have serious adverse side effects, and have had to be withdrawn. When less invasive methods have failed, and the patient is at high risk for obesity related morbidity or mortality, weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and suitable for use in only a limited number of patients. It is not only obese subjects who wish to lose weight. People with weight within the recommended range, for example, in the upper part of the recommended range, may wish to reduce their weight, to bring it closer to the ideal weight. Thus, a need remains for agents that can be used to effect weight loss in overweight and obese subjects as well as subjects who are of normal weight.
A number of derivatives of peptides deriving from the pro-glucagon molecule have been proposed for use in treatment of obesity and/or diabetes. Pro-glucagon is a precursor peptide of glucagon, as well as other hormones including oxyntomodulin (OXM) and GLP1 (glucagon-like peptide 1). Glucagon is released in vivo when blood glucose levels fall low and has the activity of causing the liver to convert stored glycogen into glucose which is released into the bloodstream raising blood glucose levels. GLP1 is produced in vivo in the intestinal L cell in response to the presence of nutrients in the lumen of the gut. Once in the circulation, native GLP1 has a half-life of only a few minutes in humans due to rapid degradation by the enzyme dipeptidyl peptidase. GLP1 possesses a number of physiological functions including increasing insulin secretion from the pancreas in a glucose-dependent manner, decreasing glucagon secretion from the pancreas, inhibiting gastric emptying and decreasing food intake by increasing satiety. Increased insulin secretion leads to a decrease in circulating glucose concentration.
WO2008/086086 (Indiana University Research and Technology Corporation) discloses certain glucagon peptides which have been modified by the incorporation of charged amino acids at the carboxy terminus of the peptide. The peptides are disclosed as having enhanced aqueous solubility at a pH ranging from about 5.5 to about 8.
WO2011/075393 (Indiana University Research and Technology Corporation) discloses certain peptides having activity at the GLP1 and/or glucagon receptors, including peptides which are based on the sequence of glucagon but which are modified such that the glucagon residues at positions 18 to 24 are substituted for exendin-4 residues. Exendin-4 is a lizard venom peptide which is a structural homolog of GLP1 (50% amino acid identity) and which also has activity at the GLP-1 receptor. WO2011/075393 teaches that, in order to achieve prolonged half-life/extended duration of action, the peptides may contain acylated or alkylated amino acids.
Despite significant advances, the process of identifying substances useful as drugs remains a complex and, in many cases, unpredictable field. Compounds must possess a suitable balance of properties, for example in addition to having efficacy at the biological target of interest, they must have good in vivo pharmacokinetic properties as well as low toxicity.
The present invention is based on the discovery that analogues of glucagon containing His residues at specified positions can be administered to a subject in order to cause an alteration in energy metabolism, so as to promote weight loss. In many case the glucagon analogues of the present invention have an improved pharmacokinetic profile, having a longer duration of action than native glucagon. In particular, glucagon analogues may have an improved pharmacokinetic profile characterised by a slower increase of plasma levels following administration, a lower Cmax and/or a more stable plateau. Such a pharmacokinetic profile may be associated with a decrease in side effects such as nausea, which are associated with a rapid onset of high plasma levels. Glucagon analogues of the invention may display improved potency and/or fewer side effects compared with native glucagon. Increased potency at the glucagon receptor results in lower doses being required to decrease food intake, thereby decreasing the side effects associated with high doses.
The present invention is also based on the discovery that analogues of GLP1 containing His residues at specified positions can be administered to a subject in order to cause prolonged reduction in appetite and hence food intake, so as to promote weight loss. In many cases the GLP1 analogues of the present invention exhibit improved pharmacokinetic properties (e.g. longer duration of action) compared with native GLP1. In particular, GLP1 analogues may have an improved pharmacokinetic profile characterised by a slower increase of plasma levels following administration, a lower Cmax and/or a more stable plateau. Such a pharmacokinetic profile may be associated with a decrease in side effects such as nausea, which are associated with a rapid onset of high plasma levels. GLP1 analogues of the invention may display improved potency and/or fewer side effects compared with native GLP1. Increased potency at the GLP-1 receptor results in lower doses being required to decrease food intake, thereby decreasing the side effects associated with high doses.